tbuckley/cabot-search huggingface dataset:
Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications
Authors: Miguel A Martin-Serrano, Benjamin Kepecs, Miguel Torres-Martin, Emily R Bramel, Philipp K Haber, Elliot Merritt, Alexander Rialdi, Nesteene Joy Param, Miho Maeda, Katherine E Lindblad, James K Carter, Marina Barcena-Varela, Vincenzo Mazzaferro, Myron Schwartz, Silvia Affo, Robert F Schwabe, Augusto Villanueva, Ernesto Guccione, Scott L Friedman, Amaia Lujambio, Anna Tocheva, Josep M Llovet, Swan N Thung, Alexander M Tsankov, Daniela Sia
Journal: Gut (2022)

Objective The diversity of the tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) has not been comprehensively assessed. We aimed to generate a novel molecular iCCA classifier that incorporates elements of the stroma, tumour and immune microenvironment (‘STIM’ classification). Design We applied virtual deconvolution to transcriptomic data from ~900 iCCAs, enabling us to devise a novel classification by selecting for the most relevant TME components. Murine models were generated through hydrodynamic tail vein injection and compared with the human disease. Results iCCA is composed of five robust STIM classes encompassing both inflamed (35%) and non-inflamed profiles (65%). The inflamed classes, named immune classical (~10%) and inflammatory stroma (~25%), differ in oncogenic pathways and extent of desmoplasia, with the inflammatory stroma showing T cell exhaustion, abundant stroma and KRAS mutations (p&lt;0.001). Analysis of cell–cell interactions highlights cancer-associated fibroblast subtypes as potential mediators of immune evasion. Among the non-inflamed classes, the desert-like class (~20%) harbours the lowest immune infiltration with abundant regulatory T cells (p&lt;0.001), whereas the hepatic stem-like class (~35%) is enriched in ‘M2-like’ macrophages, mutations in IDH1/2 and BAP1, and FGFR2 fusions. The remaining class ( tumour classical : ~10%) is defined by cell cycle pathways and poor prognosis. Comparative analysis unveils high similarity between a KRAS/p19 murine model and the inflammatory stroma class (p=0.02). The KRAS-SOS inhibitor, BI3406, sensitises a KRAS -mutant iCCA murine model to anti-PD1 therapy. Conclusions We describe a comprehensive TME-based stratification of iCCA. Cross-species analysis establishes murine models that align closely to human iCCA for the preclinical testing of combination strategies.
Unified European support framework to sustain the HIV cascade of care for people living with HIV including in displaced populations of war-struck Ukraine
Authors: Marta Vasylyev, Agata Skrzat-Klapaczyńska, Jose I Bernardino, Oana Săndulescu, Christine Gilles, Agnès Libois, Adrian Curran, Christoph D Spinner, Dominic Rowley, Markus Bickel, Maximilian C Aichelburg, Silvia Nozza, Annemarie Wensing, Tristan J Barber, Laura Waters, Carlijn Jordans, Wichor Bramer, Botond Lakatos, Lidia Tovba, Tetyana Koval, Tetyana Kyrychenko, Kostyantyn Dumchev, Vira Buhiichyk, Pavlo Smyrnov, Svitlana Antonyak, Sergii Antoniak, Tetyana I Vasylyeva, Alyona Mazhnaya, Justyna Kowalska, Sanjay Bhagani, Casper Rokx
Journal: The Lancet HIV (2022)
Matter Over Mind
Authors: John M. Luce
Journal: Annals of Internal Medicine (2022)

On Being a DoctorMay 2022Matter Over MindJohn M. Luce, MDJohn M. Luce, MDDepartment of Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, and University of California, San Francisco, San Francisco, CaliforniaSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M21-4674 Audio Reading - “Matter Over Mind” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Matter Over Mind” by John M. Luce, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail I am a retired physician, 79 years of age, living in San Francisco with my wife, formerly a physician herself. Late last year, my 76-year-old sister called me in tears from an extended-care facility near her home in Massachusetts. She was residing at the facility because of debility caused by a metastatic adenocarcinoma of the lung that was diagnosed 2 months earlier after she developed a cough. She was now receiving opioids for severe abdominal pain related to a fecal impaction that was being treated. Although my sister had just received her first dose of oral targeted therapy appropriate for ... Author, Article, and Disclosure InformationAffiliations: Department of Medicine, Zuckerberg San Francisco General Hospital and Trauma Center, and University of California, San Francisco, San Francisco, CaliforniaCorresponding Author: John M. Luce, MD; e-mail, [email protected]com. PreviousarticleNextarticle Advertisement Audio Reading - “Matter Over Mind” Audio. Michael A. Lacombe, MD, Annals Associate Editor, reads “Matter Over Mind” by John M. Luce, MD Your browser does not support the audio element. Audio player progress bar Step backward in current audio track Play current audio trackPause current audio track Step forward in current audio track Mute current audio trackUnmute current audio track 00:00/ FiguresReferencesRelatedDetails Metrics May 2022Volume 175, Issue 5Page: 759-760 ePublished: 17 May 2022 Issue Published: May 2022 Copyright & PermissionsCopyright © 2022 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Ex silico engineering of cystine-dense peptides yielding a potent bispecific T cell engager
Authors: Zachary R. Crook, Emily J. Girard, Gregory P. Sevilla, Mi-Youn Brusniak, Peter B. Rupert, Della J. Friend, Mesfin M. Gewe, Midori Clarke, Ida Lin, Raymond Ruff, Fiona Pakiam, Tinh-Doan Phi, Ashok Bandaranayake, Colin E. Correnti, Andrew J. Mhyre, Natalie W. Nairn, Roland K. Strong, James M. Olson
Journal: Science Translational Medicine (2022)

Cystine-dense peptides (CDPs) are a miniprotein class that can drug difficult targets with high affinity and low immunogenicity. Tools for their design, however, are not as developed as those for small-molecule and antibody drugs. CDPs have diverse taxonomic origins, but structural characterization is lacking. Here, we adapted Iterative Threading ASSEmbly Refinement (I-TASSER) and Rosetta protein modeling software for structural prediction of 4298 CDP scaffolds and performed in silico prescreening for CDP binders to targets of interest. Mammalian display screening of a library of docking-enriched, methionine and tyrosine scanned (DEMYS) CDPs against PD-L1 yielded binders from four distinct CDP scaffolds. One was affinity-matured, and cocrystallography yielded a high-affinity ( K D = 202 pM) PD-L1–binding CDP that competes with PD-1 for PD-L1 binding. Its subsequent incorporation into a CD3-binding bispecific T cell engager produced a molecule with pM-range in vitro T cell killing potency and which substantially extends survival in two different xenograft tumor-bearing mouse models. Both in vitro and in vivo, the CDP-incorporating bispecific molecule outperformed a comparator antibody-based molecule. This CDP modeling and DEMYS technique can accelerate CDP therapeutic development.
Locally secreted BiTEs complement CAR T cells by enhancing killing of antigen heterogeneous solid tumors
Authors: Yibo Yin, Jesse L Rodriguez, Nannan Li, Radhika Thokala, MacLean P Nasrallah, Li Hu, Logan Zhang, Jiasi Vicky Zhang, Meghan T Logun, Devneet Kainth, Leila Haddad, Yang Zhao, Tong Wu, Emily X Johns, Yu Long, Hongsheng Liang, Jiping Qi, Xiangtong Zhang, Zev A Binder, Zhiguo Lin, Donald M O'Rourke
Journal: Molecular Therapy (2022)

Bispecific T cell engagers (BiTEs) are bispecific antibodies that redirect T cells to target antigen-expressing tumors. We hypothesized that BiTE-secreting T cells could be a valuable therapy in solid tumors, with distinct properties in mono- or multi-valent strategies incorporating chimeric antigen receptor (CAR) T cells. Glioblastomas represent a good model for solid tumor heterogeneity, representing a significant therapeutic challenge. We detected expression of tumor-associated epidermal growth factor receptor (EGFR), EGFR variant III, and interleukin-13 receptor alpha 2 (IL13Rα2) on glioma tissues and cancer stem cells. These antigens formed the basis of a multivalent approach, using a conformation-specific tumor-related EGFR targeting antibody (806) and Hu08, an IL13Rα2-targeting antibody, as the single chain variable fragments to generate new BiTE molecules. Compared with CAR T cells, BiTE T cells demonstrated prominent activation, cytokine production, and cytotoxicity in response to target-positive gliomas. Superior response activity was also demonstrated in BiTE-secreting bivalent T cells compared with bivalent CAR T cells in a glioma mouse model at early phase, but not in the long term. In summary, BiTEs secreted by mono- or multi-valent T cells have potent anti-tumor activity in vitro and in vivo with significant sensitivity and specificity, demonstrating a promising strategy in solid tumor therapy.
Paying for artificial intelligence in medicine
Authors: Ravi B. Parikh, Lorens A. Helmchen
Journal: npj Digital Medicine (2022)

Over the past 7 years, regulatory agencies have approved hundreds of artificial intelligence (AI) devices for clinical use. In late 2020, payers began reimbursing clinicians and health systems for each use of select image-based AI devices. The experience with traditional medical devices has shown that per-use reimbursement may result in the overuse use of AI. We review current models of paying for AI in medicine and describe five alternative and complementary reimbursement approaches, including incentivizing outcomes instead of volume, utilizing advance market commitments and time-limited reimbursements for new AI applications, and rewarding interoperability and bias mitigation. As AI rapidly integrates into routine healthcare, careful design of payment for AI is essential for improving patient outcomes while maximizing cost-effectiveness and equity.
Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts
Authors: Bo Zhou, Arianne Caudal, Xiaoting Tang, Juan D. Chavez, Timothy S. McMillen, Andrew Keller, Outi Villet, Mingyue Zhao, Yaxin Liu, Julia Ritterhoff, Pei Wang, Stephen C. Kolwicz, Wang Wang, James E. Bruce, Rong Tian
Journal: Journal of Clinical Investigation (2022)

In hypertrophied and failing hearts, fuel metabolism is reprogrammed to increase glucose metabolism, especially glycolysis. This metabolic shift favors biosynthetic function at the expense of ATP production. Mechanisms responsible for the switch are poorly understood. We found that inhibitory factor 1 of the mitochondrial FoF1-ATP synthase (ATPIF1), a protein known to inhibit ATP hydrolysis by the reverse function of ATP synthase during ischemia, was significantly upregulated in pathological cardiac hypertrophy induced by pressure overload, myocardial infarction, or α-adrenergic stimulation. Chemical cross-linking mass spectrometry analysis of hearts hypertrophied by pressure overload suggested that increased expression of ATPIF1 promoted the formation of FoF1-ATP synthase nonproductive tetramer. Using ATPIF1 gain- and loss-of-function cell models, we demonstrated that stalled electron flow due to impaired ATP synthase activity triggered mitochondrial ROS generation, which stabilized HIF1α, leading to transcriptional activation of glycolysis. Cardiac-specific deletion of ATPIF1 in mice prevented the metabolic switch and protected against the pathological remodeling during chronic stress. These results uncover a function of ATPIF1 in nonischemic hearts, which gives FoF1-ATP synthase a critical role in metabolic rewiring during the pathological remodeling of the heart.
Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia
Authors: Saara Laukkanen, Alexandra Veloso, Chuan Yan, Laura Oksa, Eric J. Alpert, Daniel Do, Noora Hyvärinen, Karin McCarthy, Abhinav Adhikari, Qiqi Yang, Sowmya Iyer, Sara P. Garcia, Annukka Pello, Tanja Ruokoranta, Sanni Moisio, Sadiksha Adhikari, Jeffrey A. Yoder, Kayleigh Gallagher, Lauren Whelton, James R. Allen, Alex H. Jin, Siebe Loontiens, Merja Heinäniemi, Michelle Kelliher, Caroline A. Heckman, Olli Lohi, David M. Langenau
Journal: Blood (2022)
Optimize Local Therapy for Oligometastatic and Oligoprogressive Non–Small Cell Lung Cancer to Enhance Survival
Authors: Joe Y. Chang, Vivek Verma
Journal: Journal of the National Comprehensive Cancer Network (2022)

Metastatic non–small cell lung cancer (NSCLC) is highly heterogeneous, and there are patients with limited areas of metastases (oligometastases) or progression (oligoprogression) whose natural history and prognosis can be considerably more favorable. As a result, local therapy may offer these patients a chance at clinically meaningful disease control and/or cure. This review begins by describing the current status of the existing prospective data, including evidence of overall survival improvements from multiple randomized trials. Given the nascence of this realm, the review then examines ongoing controversies and unresolved issues regarding local therapy for oligometastatic and oligoprogression. First, the role of local therapy in the setting of targeted therapies and immunotherapy is discussed, because most published randomized trials of local therapy have been performed in the context of chemotherapy, which is no longer the standard of care for most patients with metastatic NSCLC. Refining patient selection for local therapy is then reviewed, including clinical factors (such as control of the primary and regional lymph node sites, the heterogeneous definitions of oligometastases/oligoprogression, and the underrepresentation of brain metastases in existing randomized data) and novel pathologic/molecular biomarkers. Next, because there also remains no consensus regarding the optimal modality of local therapy, the advantages and disadvantages of stereotactic radiotherapy, surgery, and other ablative techniques are discussed. Subsequently, methods to optimize radiotherapy are examined, including controversies regarding the optimal dose/fractionation and timing/sequencing scheme. A discussion regarding potentially extending the existing data to polymetastatic NSCLC follows. The review concludes with remarks regarding prudently designing randomized trials of local therapy going forward, including the benefits and drawbacks of specific endpoints meriting further testing in this unique population.
Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy
Authors: Haixia Long, Qingzhu Jia, Liuyang Wang, Wenfeng Fang, Zhongyu Wang, Tao Jiang, Fei Zhou, Zheng Jin, Jiani Huang, Li Zhou, Chunyan Hu, Xinxin Wang, Jin Zhang, Yujie Ba, Yujie Gong, Xianghua Zeng, Dong Zeng, Xingxing Su, Peter B. Alexander, Li Wang, Limei Wang, Yisong Y. Wan, Xiao-Fan Wang, Li Zhang, Qi-Jing Li, Bo Zhu
Journal: Cancer Cell (2022)
Diagnostic evaluation and cardiopulmonary exercise test findings in young athletes with persistent symptoms following COVID-19
Authors: Nathaniel Moulson, Sarah K Gustus, Christina Scirica, Bradley J Petek, Caroyln Vanatta, Timothy W Churchill, James Sawalla Guseh, Aaron Baggish, Meagan M Wasfy
Journal: British Journal of Sports Medicine (2022)

Objectives Persistent or late-onset cardiopulmonary symptoms following COVID-19 may occur in athletes despite a benign initial course. We examined the yield of cardiac evaluation, including cardiopulmonary exercise testing (CPET), in athletes with cardiopulmonary symptoms after COVID-19, compared CPETs in these athletes and those without COVID-19 and evaluated longitudinal changes in CPET with improvement in symptoms. Methods This prospective cohort study evaluated young (18–35 years old) athletes referred for cardiopulmonary symptoms that were present&gt;28 days from COVID-19 diagnosis. CPET findings in post-COVID athletes were compared with a matched reference group of healthy athletes without COVID-19. Post-COVID athletes underwent repeat CPET between 3 and 6 months after initial evaluation. Results Twenty-one consecutive post-COVID athletes with cardiopulmonary symptoms (21.9±3.9 years old, 43% female) were evaluated 3.0±2.1 months after diagnosis. No athlete had active inflammatory heart disease. CPET reproduced presenting symptoms in 86%. Compared with reference athletes (n=42), there was similar peak VO 2 but a higher prevalence of abnormal spirometry (42%) and low breathing reserve (42%). Thirteen athletes (62%) completed longitudinal follow-up (4.8±1.9 months). The majority (69%) had reduction in cardiopulmonary symptoms, accompanied by improvement in peak VO 2 and oxygen pulse, and reduction in resting and peak heart rate (all p&lt;0.05). Conclusion Despite a high burden of cardiopulmonary symptoms after COVID-19, no athlete had active inflammatory heart disease. CPET was clinically useful to reproduce symptoms with either normal testing or identification of abnormal spirometry as a potential therapeutic target. Improvement in post-COVID symptoms was accompanied by improvements in CPET parameters.
Mg-based materials diminish tumor spreading and cancer metastases
Authors: Philipp Globig, Roshani Madurawala, Regine Willumeit-Römer, Fernanda Martini, Elisa Mazzoni, Bérengère J.C. Luthringer-Feyerabend
Journal: Bioactive Materials (2022)

Cancer metastases are the most common causes of cancer-related deaths. The formation of secondary tumors at different sites in the human body can impair multiple organ function and dramatically decrease the survival of the patients. In this stage, it is difficulty to treat tumor growth and spreading due to arising therapy resistances. Therefore, it is important to prevent cancer metastases and to increase subsequent cancer therapy success. Cancer metastases are conventionally treated with radiation or chemotherapy. However, these treatments elicit lots of side effects, wherefore novel local treatment approaches are currently discussed. Recent studies already showed anticancer activity of specially designed degradable magnesium (Mg) alloys by reducing the cancer cell proliferation. In this work, we investigated the impact of these Mg-based materials on different steps of the metastatic cascade including cancer cell migration, invasion, and cancer-induced angiogenesis. Both, Mg and Mg-6Ag reduced cell migration and invasion of osteosarcoma cells in coculture with fibroblasts. Furthermore, the Mg-based materials used in this study diminished the cancer-induced angiogenesis. Endothelial cells incubated with conditioned media obtained from these Mg and Mg-6Ag showed a reduced cell layer permeability, a reduced proliferation and inhibited cell migration. The tube formation as a last step of angiogenesis was stimulated with the presence of Mg under normoxia and diminished under hypoxia.
Stromal Notch ligands foster lymphopenia-driven functional plasticity and homeostatic proliferation of naive B cells
Authors: Daniela Gómez Atria, Brian T. Gaudette, Jennifer Londregan, Samantha Kelly, Eric Perkey, Anneka Allman, Bhaskar Srivastava, Ute Koch, Freddy Radtke, Burkhard Ludewig, Christian W. Siebel, Russell J.H. Ryan, Tanner F. Robertson, Janis K. Burkhardt, Warren S. Pear, David Allman, Ivan Maillard
Journal: Journal of Clinical Investigation (2022)

In lymphopenic environments, secondary lymphoid organs regulate the size of B and T cell compartments by supporting the homeostatic proliferation of mature lymphocytes. The molecular mechanisms underlying these responses and their functional consequences remain incompletely understood. To evaluate homeostasis of the mature B cell pool during lymphopenia, we turned to an adoptive transfer model of purified follicular B cells into Rag2–/– mouse recipients. Highly purified follicular B cells transdifferentiated into marginal zone–like B cells when transferred into Rag2–/– lymphopenic hosts but not into wild-type hosts. In lymphopenic spleens, transferred B cells gradually lost their follicular phenotype and acquired characteristics of marginal zone B cells, as judged by cell surface phenotype, expression of integrins and chemokine receptors, positioning close to the marginal sinus, and an ability to rapidly generate functional plasma cells. Initiation of follicular to marginal zone B cell transdifferentiation preceded proliferation. Furthermore, the transdifferentiation process was dependent on Notch2 receptors in B cells and expression of Delta-like 1 Notch ligands by splenic Ccl19-Cre+ fibroblastic stromal cells. Gene expression analysis showed rapid induction of Notch-regulated transcripts followed by upregulated Myc expression and acquisition of broad transcriptional features of marginal zone B cells. Thus, naive mature B cells are endowed with plastic transdifferentiation potential in response to increased stromal Notch ligand availability during lymphopenia.
CD4<sup>+</sup>T-cell epitope-based heterologous prime-boost vaccination potentiates anti-tumor immunity and PD-1/PD-L1 immunotherapy
Authors: Minglu Xiao, Luoyingzi Xie, Guoshuai Cao, Shun Lei, Pengcheng Wang, Zhengping Wei, Yuan Luo, Jingyi Fang, Xingxing Yang, Qizhao Huang, Lifan Xu, Junyi Guo, Shuqiong Wen, Zhiming Wang, Qing Wu, Jianfang Tang, Lisha Wang, Xiangyu Chen, Cheng Chen, Yanyan Zhang, Wei Yao, Jianqiang Ye, Ran He, Jun Huang, Lilin Ye
Journal: Journal for ImmunoTherapy of Cancer (2022)

Antitumor therapeutic vaccines are generally based on antigenic epitopes presented by major histocompatibility complex (MHC-I) molecules to induce tumor-specific CD8+ T cells. Paradoxically, continuous T cell receptor (TCR) stimulation from tumor-derived CD8+ T-cell epitopes can drive the functional exhaustion of tumor-specific CD8+ T cells. Tumor-specific type-I helper CD4+ T (TH1) cells play an important role in the population maintenance and cytotoxic function of exhausted tumor-specific CD8+ T cells in the tumor microenvironment. Nonetheless, whether the vaccination strategy targeting MHC-II-restricted CD4+ T-cell epitopes to induce tumor-specific TH1 responses can confer effective antitumor immunity to restrain tumor growth is not well studied. Here, we developed a heterologous prime-boost vaccination strategy to effectively induce tumor-specific TH1 cells and evaluated its antitumor efficacy and its capacity to potentiate PD-1/PD-L1 immunotherapy.Listeria monocytogenes vector and influenza A virus (PR8 strain) vector stably expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein-specific I-Ab-restricted CD4+ T cell epitope (GP61-80) or ovalbumin-specific CD4+ T cell epitope (OVA323-339) were constructed and evaluated their efficacy against mouse models of melanoma and colorectal adenocarcinoma expressing lymphocytic choriomeningitis virus glycoprotein and ovalbumin. The impact of CD4+ T cell epitope-based heterologous prime-boost vaccination was detected by flow-cytometer, single-cell RNA sequencing and single-cell TCR sequencing.CD4+ T cell epitope-based heterologous prime-boost vaccination efficiently suppressed both mouse melanoma and colorectal adenocarcinoma. This vaccination primarily induced tumor-specific TH1 response, which in turn enhanced the expansion, effector function and clonal breadth of tumor-specific CD8+ T cells. Furthermore, this vaccination strategy synergized PD-L1 blockade mediated tumor suppression. Notably, prime-boost vaccination extended the duration of PD-L1 blockade induced antitumor effects by preventing the re-exhaustion of tumor-specific CD8+ T cells.CD4+ T cell epitope-based heterologous prime-boost vaccination elicited potent both tumor-specific TH1 and CTL response, leading to the efficient tumor control. This strategy can also potentiate PD-1/PD-L1 immune checkpoint blockade (ICB) against cancer.